Daptomycin (DAP) represents an interesting alternative to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Different mechanisms of DAP resistance have been described; however, in vivo-acquired resistance is uncharacterized. This study described the phenotypic and genotypic evolution of MRSA strains that became resistant to DAP in two unrelated patients with bacteremia under DAP treatment, in two hospitals in the South of France. DAP MICs were determined using broth microdilution method on the pairs of isogenic (DAP-S/DAP-R) S. aureus isolated from bloodstream cultures. Whole genome sequencing was carried out using Illumina MiSeq Sequencing system. The two cases revealed DAP-R acquisition by MRSA strains within three weeks in patients treated by DAP. The isolates belonged to the widespread ST5 (patient A) and ST8 (patient B) lineages and were of spa-type t777 and t622, respectively. SNP analysis comparing each DAP-S/DAP-R pair confirmed that the isolates were isogenic. The causative mutations were identified in MprF (Multiple peptide resistance Factor) protein: L826F (Patient A) and S295L (Patient B), and in Cls protein: R228H (Patient B). These proteins encoded both proteins of the lipid biosynthetic enzymes. The resistance to DAP is particularly poorly described whereas DAP is highly prescribed to treat MRSA. Our study highlights the non-systematic cross-resistance between DAP and glycopeptides and the importance of monitoring DAP MIC in persistent MRSA bacteremia.

Multiple modes of interventions are available when implementing an antibiotic stewardship program (ASP), however, their complementarity has not yet been assessed. In a 938-bed hospital, we sequentially implemented four combined modes of interventions over one year, centralized by one infectious diseases specialist (IDS): (1) on-request infectious diseases specialist consulting service (IDSCS), (2) participation in intensive care unit meetings, (3) IDS intervention triggered by microbiological laboratory meetings, and (4) IDS intervention triggered by pharmacist alert. We assessed the complementarity of the different cumulative actions through quantitative and qualitative analysis of all interventions traced in the electronic medical record. We observed a quantitative and qualitative complementarity between interventions directly correlating to a decrease in antibiotic use. Quantitatively, the number of interventions has doubled after implementation of IDS intervention triggered by pharmacist alert. Qualitatively, these kinds of interventions led mainly to de-escalation or stopping of antibiotic therapy (63%) as opposed to on-request IDSCS (32%). An overall decrease of 14.6% in antibiotic use was observed (p = 0.03). Progressive implementation of the different interventions showed a concrete complementarity of these actions. Combined actions in ASPs could lead to a significant decrease in antibiotic use, especially regarding critical antibiotic prescriptions, while being well accepted by prescribers.